Age-related muscle atrophy (i.e., sarcopenia) affects the entire population of adults 65+ years of age. Sarcopenia results in functional disability, loss of independence, and increased all-cause mortality in older adults. Currently, the most effective strategy for restoring muscle mass in sarcopenic, older adults is resistance exercise training (RT), which results in marked myofiber hypertrophy in most adults. However, the extent of muscle regrowth is extremely variable between individuals, with some individuals failing to increase myofiber hypertrophy following long-term RT (i.e., nonresponders). The extent of myofiber hypertrophy is typically less in older adults when compared to young following RT, and recent data from the Bamman laboratory have shown that ~40% of sarcopenic, older adults are nonresponders to RT. This is particularly concerning; as these individuals are in desperate need of muscle regrowth, and without adjuvant therapies, sarcopenic nonresponders will inevitably suffer the negative consequences of muscle atrophy. It is therefore of great importance to develop effective strategies to regrow muscle in older, sarcopenic adults who respond poorly to RT alone. Based on novel genomic and proteomic preliminary data, it is our central hypothesis that the nonresponder phenotype is driven by aberrant, intrinsic cellular responses to the homeostatic challenges imposed by RT (e.g., mechanical and metabolic stress). This hypothesis will be tested in a series of in vitro experiments using primary myogenic cells harvested from 60-75 y sarcopenic responders and nonresponders. Differentiated, primary myotubes will be subjected to various anabolic and stress-generating stimuli with the following specific aims in mind: Specific Aim 1. We will determine key translational signaling processes associated with impaired protein synthesis responses to mechanical stress in myotubes from nonresponders. It is expected that defective translation initiation signaling and possibly autocrine growth factor signaling regulate the blunted protein synthesis response in nonresponders myotubes. Specific Aim 2. We will determine if blunted hypertrophy of nonresponder myotubes is linked with an impaired capacity for cellular energy production. Inability to sustain sufficient energy production for protein synthesis is likely to be a major caue of attenuated hypertrophy in nonresponder myotubes. These experiments are fully expected to advance our understanding of the mechanisms responsible for the nonresponder phenotype. The knowledge gained from these experiments will be valuable for developing adjuvant therapies to enhance RT-induced muscle regrowth in sarcopenic, older adults. PUBLIC HEALTH RELEVANCE: The U.S. and world population of aging adults is growing rapidly. Substantial declines in skeletal muscle mass (i.e. atrophy) are unfortunately common place in the aging population, and this atrophy increases disability and all-cause mortality. The planned experiments are expected to substantially improve treatment strategies, which will lead to enhanced quality of life and reduced disease/disability risk.